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WORLD INTELLECTUAL PROPERTY ORGANIZATION
International Bureau

PCX

INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)

(51) International Patent Classification 6
GOIN 27/26, 27/02, 27/28

(11) International Publication Number:
(43) International Publication Date:

WO 99/32881

1 July 1999 (01.07.99)

(21) International Application Number: PCT/US98/27203

(22) International Filing Date: 21 December 1998 (2L12.98)

(30) Priority Data:

08/996,280

22 December 1997 (22.1 2.97) US

(63) Related by Continuation (CON) or Continue tion-in-Part
(CIP) to Earlier Application

US 08/996,280 (CIP)

Filed on 22 December 1 997 (22. 1 2.97)

(71) Applicant ijor all designated States except US): ROCHE

DIAGNOSTICS CORPORATION [US/US]; 9115 Hague
Road. P.O. Box 50528, Indianapolis, IN 46250-0528 (US).

(72) Inventors; and

(75) Inventors/Applicants (for US only): BEATY, Terry, Allen
[US/US]; 7251 Lakeside Drive, Indianapolis, IN 46278
(US). KUHN, Lance, Scott [US/US]; 8334 Barstow Drive,
Fishers, IN 46038 (US). SVETNIK, Vladimir [US/US]; 539
Cedar Lake Court, Carmel, IN 46032 (US). BURKE, David,
W. [US/US]; Apartment D, 1931 Madison Court, Carmel,
IN 46032 (US).

(74) Agent: CONARD, Richard, D.; Barnes & Thomburg, 1 1 South
Meridian Street, Indianapolis, IN 46204 (US).

(81) Designated States: AL, AM, AT, AU, AZ, BA, BB, BO, BR,
BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, GD,
GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP,
KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK,
MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG,
SI, SK, SL, TJ, TM, TR, TT, UA, UG, US, UZ, VN, YU,
ZW, ARIPO patent (GH, GM, KE, LS, MW, SD, SZ, UG,
ZW). Eurasian patent (AM, AZ, BY, KG, KZ, MD, RU, TJ,
TM), European patent (AT. BE, CH, CY, DE, DK, ES, FI,
FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OAPI patent
(BF, BJ, CF. CG, CI, CM, GA, GN, GW, ML, MR, NE,
SN, TD, TG),

Published

With international search report.

(54) Title: METER

(57) Abstract

An apparatus (31, 32, 132) and
method for determining the concentration
of a medically significant component (for
example, glucose) of a biological fluid (for
example, blood) comprise providing a cell
(3 1 ) for receiving a sample of the fluid (for
example, blood). The cell (31) supports
a chemistry which reacts with the medi-
cally significant component (for example,
glucose), and first and second terminals
across which the reaction of the chem-
istry with the medically significant com-
ponent can be assessed. An instrument
(32, 132) has first (34-2, 134-2) and sec-
ond (34-3, 134-3) terminals complemen-
tary to the first and second terminals, re-
spectively, of the cell (31). An assessment
controller (52, 54, 148, 158) is provided.
The apparatus determines the type of sam-
ple and the concentration of a medically
significant component of the sample.

FOR THE PURPOSES OF INFORMATION ONLY

Codes used to identify States party to the PCT on the front pages of pamphlets publishing international applications under the PCT.

Albania

Spain

Lesotho

Slovenia

Armenia

Finland

Lithuania

Slovakia

Austria

France

Luxembourg

Senegal

Australia

Gabon

Latvia

Swaziland

Azerbaijan

United Kingdom

Monaco

Chad

Bosnia and Herzegovina

Georgia

Republic of Moldova

Togo

Barbados

Ghana

Madagascar

Tajikistan

Belgium

Guinea

The former Yugoslav

Turkmenistan

Burkina Faso

Greece

Republic of Macedonia

Turkey

Bulgaria

Hungary

Mali

Trinidad and Tobago

Benin

Ireland

Mongolia

Ukraine

Brazil

Israel

Mauritania

Uganda

Belarus

Iceland

Malawi

United States of America

Canada

Italy

Mexico

Uzbekistan

Central African Republic

Japan

Niger

Viet Nam

Congo

Kenya

Netherlands

Yugoslavia

Switzerland

Kyrgyzstan

Norway

Zimbabwe

Cdte d'lvoire

Democratic People's

New Zealand

Cameroon

Republic of Korea

Poland

China

Republic of Korea

Portugal

Cuba

Kazakstan

Romania

Czech Republic

Saint Lucia

Russian Federation

Germany

Liechtenstein

Sudan

Denmark

Sri Lanka

Sweden

Estonia

Liberia

Singapore

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METER

Background of the Invention

This invention relates to methods and apparatus for improving the
5 accuracy of measurements made with instruments of the type described in, for

example, U. S. Patents: 5,243,516; 5,288,636; 5,352,351; 5,385,846; and 5,508,171.

The invention is disclosed in the context of such an instrument, but is believed to be

useful in other instruments of this general type as well.

There are a number of instruments for the determination of the
10 concentrations of biologically significant components of bodily fluids, such as, for

example, the glucose concentration of blood. There are, for example, the instruments

described in U. S. Patents: 3,770,607; 3,838,033; 3,902,970; 3,925,183; 3,937,615;

4,005,002; 4,040,908; 4,086,631; 4,123,701; 4,127,448; 4,214,968; 4,217,196;

4,224,125; 4,225,410; 4,230,537; 4,260,680; 4,263,343; 4,265,250; 4,273,134;
15 4,301,412; 4,303,887; 4,366,033; 4,407,959; 4,413,628; 4,420,564; 4,431,004;

4,436,094; 4,440,175; 4,477,314; 4,477,575; 4,499,423; 4,517,291; 4,654,197;

4,671,288; 4,679,562; 4,682,602; 4,703,756; 4,711,245; 4,734,184; 4,750,496;

4,759,828; 4,789,804; 4,795,542; 4,805,624; 4,816,224; 4,820,399; 4,897,162;

4,897,173; 4,919,770; 4,927,516; 4,935,106; 4,938,860; 4,940,945; 4,970,145;
20 4,975,647; 4,999,582; 4,999,632; 5,108,564; 5,128,015; 5,243,516; 5,269,891;

5,288,636; 5,312,762; 5,352,351; 5,385,846; 5,395,504; 5,469,846; 5,508,171;

5,508,203; and 5,509,410: German Patent Specification 3,228,542: European Patent

Specifications: 206,218; 230,472; 241,309; 255,291; and, 471,986: and, Japanese

Pubhshed Patent Applications JP 63-128,252 and 63-1 1 1,453. There are also the
25 methods and apparatus described in: Talbott, et al, "A New Microchemical Approach

to Amperometric Analysis," Microchemical Journal, Vol. 37, pp. 5-12 (1988); Morris,

et al, "An Electrochemical Capillary Fill Device for the Analysis of Glucose

Incorporating Glucose Oxidase and Ruthenium (III) Hexamine as Mediator,

Electroanalysis," Vol. 4, pp. 1-9 (1992); Cass, et al, "Ferrocene-Mediated Enzyme
30 Electrode for Amperometric Determination of Glucose," Anal. Chem., Vol. 56, pp.

667-671 (1984); Zhao, "Contributions of Suspending Medium to Electrical

Impedance of Blood," Biochimica et Biophysica Acta, Vol. 1201, pp. 179-185 (1994);

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Zhao, "Electrical Impedance and Haematocrit of Human Blood with Various
Anticoagulants," Physiol. Meas., Vol. 14, pp. 299-307 (1993); MuUer, et al.,
"Influence of Hematocrit and Platelet Coxant on Impedance and Reactivity of Whole
Blood for Electrical Aggregometry," Journal of Pharmacological and Toxicological
5 Methods, Vol 34, pp. 17-22 (1995); Preidel, et al, "In Vitro Measurements with

Electrocataiytic Glucose Sensor in Blood," Biomed. Biochim. Acta, Vol. 48, pp. 897-
903 (1989); Preidel, et al, "Glucose Measurements by Electrocataiytic Sensor in the
Extracorporeal Blood Circulation of a Sheep," Sensors and Actuators B, Vol. 2,
pp.257-263 (1990); Saeger, et al, "Influence of Urea on the Glucose Measurement by

10 Electrocataiytic Sensor in the Extracorporeal Blood Circulation of a Sheep," Biomed.
Biochim. Acta, Vol. 50, pp. 885-891 (1991); Kasapbasioglu, et al, "An Impedance
Based Ultra-Thin Platinum Island Film Glucose Sensor," Sensors and Actuators B,
Vol. 13-14, pp. 749-751 (1993); Beyer, et al, "Development and Application of aNew
Enzyme Sensor Type Based on the ElS-Capacitance Structure for Bioprocess

15 Control," Biosensors & Bioelectronics, Vol. 9, pp. 17-21 (1994); Mohri, et al,

"Characteristic Response of Electrochemical Nonlinearity to Taste Compounds with a
Gold Electrode Modified with 4-Aminobenzenethiol," Bull. Chem. Soc. Jpn., Vol. 66,
pp. 1328-1332 (1993); Cardosi, et al, "The Realization of Electron Transfer from
Biological Molecules to Electrodes. " Biosensors Fundamentals and Applications , chapt.

20 15 (Turner, et al, eds., Oxford University Press, 1987); Mell, et al, "Amperometric
Response Enhancement of the Immobihzed Glucose Oxidase Enzyme Electrode,"
Analytical Chemistry, Vol. 48, pp. 1597-1601 (Sept. 1976); Mell, et al, "A Model for
the Amperometric Enzyme Electrode Obtained Through Digital Simulation and
Applied to the Immobihzed Glucose Oxidase System," Anal5^ical Chemistry, Vol. 47,

25 pp. 299-307 (Feb. 1975); Myland, et al, "Membrane-Covered Oxygen Sensors: An
Exact Treatment of the Switch-on Transient," Journal of the Electrochemical Society,
Vol. 131, pp. 1815-1823 (Aug. 1984); Bradley, et al, "Kinetic Analysis of Enzyme
Electrode Response," Anal. Chem., Vol. 56, pp. 664-667 (1984);
Koichi,"Measurements of Current-Potential Curves, 6, Cottrell Equation and its

30 Analogs. What Can We Know from Chronoamperometry?" Denki Kagaku oyobi
Kogyo Butsuri Kagaku, Vol. 54, no. 6, pp. 471-5 (1986); Williams, et al,
"Electrochemical-Enzymatic Analysis of Blood Glucose and Lactate," Analytical

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Chemistry, Vol. 42, no. 1, pp. 118-121 (Jan. 1970); and, Gebhardt, et al,
"Electrocatalytic Glucose Sensor," Siemens Forsch.-u. Entwickl.-Ber, Bd., Vol. 12,
pp. 91-95 (1983). This listing is not intended as a representation that a complete
search of all relevant prior art has been conducted, or that no better references than
5 those listed exist. Nor should any such representation be inferred.

Disclosure of the Invention

According to one aspect of the invention, an apparatus for determining
the concentration of a medically significant component of a biological fluid comprises a

1 0 cell for receiving a sample of the fluid. The cell supports a chemistry which reacts with
the medically significant component and first and second terminals across which the
reaction of the chemistry with the medically significant component can be assessed.
The apparatus fiirther comprises an instrument having first and second terminals
complementary to the first and second terminals, respectively, of the cell. Placement of

1 5 the first and second terminals of the cell in contact with the first and second terminals,
respectively, of the instrument permits the instrument to assess the reaction. The
instrument includes an assessment controller for applying across the first and second
terminals of the instrument a first signal, determining a first response of the cell to the
first signal, and determining based upon the first response whether to proceed with the

20 determination of the concentration of the medically significant component of the
biological fluid.

According to another aspect of the invention, an apparatus for
determining the concentration of a medically significant component of a biological fluid
comprises a cell for receiving a sample of the fluid. The cell supports a chemistry

25 which reacts with the medically significant component and first and second terminals
across which the reaction of the chemistry with the medically significant component
can be assessed. The apparatus fiirther comprises an instrument having first and
second terminals complementary to the first and second terminals, respectively, of the
cell. Placement of the first and second terminals of the cell in contact with the first and

30 second terminals, respectively, of the instrument permits the instrument to assess the
reaction. The instrument includes an assessment controller for applying across the first
and second terminals of the instrument a first signal, determining a first correction

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value in response of the cell to the first signal, assessing the reaction of the medically
significant component with the chemistry and combining the correction value with the
result of the reaction assessment to produce an indication of the concentration of the
medically significant component in the sample.
5 According to another aspect of the invention, an apparatus for

determining the concentration of a medically significant component of a biological fluid
comprises a cell for receiving a sample of the fluid. The cell supports a chemistry
whdch reacts with the medically significant component and first and second terminals
across which the reaction of the chemistry with the medically significant component

10 can be assessed. The apparatus fiirther comprises an instrument having first and

second terminals complementary to the first and second terminals, respectively, of the
cell. Placement of the first and second terminals of the cell in contact with the first and
second terminals, respectively, of the instrument permits the instrument to assess the
reaction. The instrument includes an assessment controller for applying across the first

1 5 and second terminals of the instrument a first signal, determining the identity of the
sample in response of the cell to the first signal, and producing an indication of the
identity of the sample.

According to yet another aspect of the invention, a method for
determining the concentration of a medically significant component of a biological fluid

20 comprises providing a cell for receiving a sample of the fluid, and providing on the cell
a chemistry which reacts with the medically significant component and first and second
terminals across which the reaction of the chemistry with the medically significant
component can be assessed. The method fiarther comprises providing an instrument
having first and second terminals complementary to the first and second terminals,

25 respectively, of the cell. Placement of the first and second terminals of the cell in

contact with the first and second terminals, respectively, of the instrument permits the
instrument to assess the reaction. The method further comprises providing in the
instrument an assessment controller, causing the assessment controller to apply across
the first and second terminals of the instrument a first signal, causing the assessment

30 controller to determine a first response of the cell to the first signal, and causing the
assessment controller to determine, based upon the first response, whether to proceed

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with the determination of the concentration of the medically significant component of
the biological fluid.

According to a further aspect of the invention, a method for
determining the concentration of a medically significant component of a biological fluid
5 comprises providing a cell for receiving a sample of the fluid, and providing on the cell
a chemistry which reacts with the medically significant component and first and second
terminals across which the reaction of the chemistry with the medically significant
component can be assessed. The method further comprises providing an instrument
having first and second terminals complementary to the first and second terminals,

10 respectively, of the cell. Placement of the first and second terminals of the cell in

15 correction value in response to the first signal, to assess the reaction of the medically
significant component with the chemistry, and to combine the correction value with the
result of the reaction assessment to produce an indication of the concentration of the
medically significant component in the sample.

According to a further aspect of the invention, a method for

20 determining the concentration of a medically significant component of a biological fluid
comprises providing a cell for receiving a sample of the fluid, and providing on the cell
a chemistry which reacts with the medically significant component and first and second
terminals across which the reaction of the chemistry with the medically significant
component can be assessed. The method further comprises providing an instrument

25 having first and second terminals complementary to the first and second terminals,
respectively, of the cell Placement of the first and second terminals of the cell in
contact with the first and second terminals, respectively, of the instrument permits the
instrument to assess the reaction. The method further comprises providing in the
instrument an assessment controller for applying across the first and second terminals

30 of the instrument a first signal, determining the identity of the sample in response of the
cell to the first signal, and producing an indication of the identity of the sample.

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lUustratively, the first signal comprises a signal having an AC
component. Further illustratively, the first signal comprises an AC signal.

Additionally illustratively, the method of, and apparatus for,
determining the correction value, the method of, and apparatus for, determining the
5 identity of the sample, and the method of, and apparatus for, determining whether to
proceed with the determination of the concentration of the medically significant
component of the biological fluid comprise the step of, and apparatus for, determining
the impedance across terminals of the cell.

10 Brief Description of the Drawings

The invention may best be understood by referring to the following
detailed description and accompanying drawings which illustrate the invention. In the
drawings:

Fig. 1 illustrates a schematic diagram of a circuit useful in
1 5 understanding the invention;

Fig. 2 illustrates a partly block and partly schematic diagram of an
instrument constructed according to the present invention;

Fig. 3 illustrates a partly block and partly schematic diagram of another
instrument constructed according to the present invention;
20 Fig. 4 illustrates a partly block and partly schematic diagram of another

instrument constructed according to the present invention;

Fig. 5 illustrates glucose concentration results achieved in several forty
second glucose concentration determinations with standard glucose test solutions;

Fig. 6 illustrates glucose concentration results achieved in several ten
25 second glucose concentration determinations with standard glucose test solutions; and.
Fig. 7 illustrates glucose concentration results achieved in several ten
second glucose concentration determinations with standard glucose test solutions.

Detailed Descriptions of Illustrative Embodiments
30 Instruments are known which employ devices such as disposable

mediated amperometric cells (sometimes referred to hereinafter as biosensors) which
provide, for example, characteristic electrical impedances when treated with biological

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fluids, blood or urine for example, having certain corresponding concentrations of
biologically significant components, such as, for example, glucose. Such measurement
systems are known to be susceptible to variations in the temperature of the biological
fluids and to interference by the presence in the biological fluids of other components,
5 known and sometimes referred to hereinafl:er as interferrents. In many cases, these
sources of error have effects on the biosensor output of the same order of magnitude
as the concentration of the component, measurement of which is sought. It may not be
possible to develop a biosensor which will measure only the concentration of the
component whose concentration is sought in the presence of these sources of error.

10 An example of this phenomenon is the hematocrit interference in a biosensor of the
type described in U. S. Patents: 5,243,516; 5,288,636; 5,352,351; 5,385,846 and,
5,508,171, with the determination of the glucose concentration of whole blood. Since
all whole blood contains red blood cells, and since the hematocrit can vary over a fairly
wide range in individuals who might wish to rely upon such biosensor testing, the

15 utility of a hematocrit-compensated glucose biosensor is clear.

Equally problematic is the sensitivity of many commercially available
biosensors to the volume of the dopant biological fluid. In the case of glucose
concentration of whole blood, for example, many presently available biosensors are
sensitive to the volume of blood with which they are doped for determination of

20 glucose concentration. Since many of the tests which are presently being conducted
using biosensors are being conducted by people who are monitoring, for example, the
glucose concentrations of their own blood, the volumes of the blood samples with
which the biosensors are doped are not predictable with a great degree of certainty.
While the careful design of the biosensor itself can prevent some errors, such as

25 undoped biosensors, substantially underdoped biosensors and substantially overdoped
biosensors, for example, it cannot practically take into account the full range of doping
volume variation.

We have discovered that measurement of the real component or the
imaginary component, or both, of the AC impedance of an appropriately designed

30 biosensor provides reasonable insight into sample temperature and the concentrations
of certain physical and chemical interferrents. In biosensors of the general tj^^es
described in U. S. Patents: 5,243,516; 5,288,636; 5,352,351; 5,385,846; 5,508,171;

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5,437,999; and, U.S.S.N, 08/985,840, filed December 5, 1997 and assigned to the
same assignee as this application, such physical interferrents include, for example,
hematocrit, and such chemical interferrents include, for example, bilirubin, uric acid
and oxygen. We have discovered that measurement of the real component or the
5 imaginary component, or both, of the AC impedance of an appropriately designed
biosensor also provides reasonable insight into the volume of a sample with which the
biosensor is doped, and the identity of that sample; that is, whether the sample is a
sample of blood or some other bodily fluid, or a sample of some control used, for
example, in calibration or troubleshooting of the instrument. We have discovered that

10 sample temperature, the concentrations of such physical and chemical interferrents, the
identity of the sample and the sample volume can be ascertained at judiciously selected
AC fi-equencies, providing reasonable isolation of the determinations of the eflfects of
sample temperature, interferrent concentrations and sample volume and identity firom
each other, and thereby increasing the accuracy of, for example, the interferrent effect

1 5 determinations, and their subsequent correction out of the indicated glucose

concentration. We have also found that the speeds at which acceptably accurate
readings of corrected glucose concentration are obtained can be markedly reduced.
The appropriately designed biosensor must be able to tolerate the determination of
these AC impedances, using, for example, AC signals having peak amplitudes in the

20 range of a few tens of millivolts, without jeopardizing the measurement of the glucose
concentration, which the biosensor will perform either before, concurrently with, or
after it performs the AC impedance determination.

By way of example only, we have determined that in biosensors of the
type described inU. S. Patents: 5,243,516; 5,288,636; 5,352,351; 5,385,846;

25 5,508,171; 5,437,999; and, U.S.S.N. 08/985,840, it is possible to employ a low-
magnitude, for example, less than about 40mV rms or so, AC signal in the range of
less than about . IHz to lOKHz or so with no DC offset to compensate for sample
temperature, hematocrit, bilirubin concentration, uric acid concentration and oxygen
concentration, and to determine identity of the sample with which the biosensor is

30 dosed, and adequacy of dosed blood sample volume for a test for glucose

concentration. We have determined, for example, that at about 1300Hz, both
hematocrit and glucose concentration have relatively little eflfect on AC impedance.

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while sample volume and sample identity have relatively substantially greater, fairly
readily ascertainable, effects on AC impedance. This provides an ideal way to
determine the adequacy of the sample volume with which the biosensor is dosed and
the identity of the sample. If the sample is determined to be blood, and the sample
5 volume is determined to be inadequate to test meaningfully for hematocrit, glucose
concentration, and so on, the test is discontinued and the user is notified of the
discontinuance of the test.

We have determined that the combined effect of sample temperature
and hematocrit can fairly effectively be isolated from other physical and chemical

1 0 interferrents of interest using frequencies in the range of from about 2KHz to about
lOKHz. So, for example, once the adequacy of the sample volume for test has been
established, a 2KHz signal can be apphed to the biosensor and the real and imaginary
components of impedance of the biosensor/sample system can be determined. This
indicated impedance can be adjusted by an experimentally determined scaling factor

15 governed by, among other things, the characteristics of the biosensor and the
instrument, and combined with an indicated glucose concentration to arrive at a
glucose concentration compensated for the combined effects of sample temperature
and hematocrit.

These determinations illustratively are made before the amperometric
20 determination of the glucose concentration of the blood sample. DC offset may be
avoided, if necessary, to reduce the hkelihood of affecting the amperometric
determination of the glucose concentration which, it must be remembered, is going to
be conducted subsequently in the illustrated embodiments. Similar procedures can be
conducted, again in the illustrated embodiments before the amperometric
25 determination of the glucose concentration, to determine the concentrations of other
interferrents with chemistry for the glucose concentration determination, such as
bilirubin, uric acid and oxygen. These determinations are conducted at frequencies at
which their effects upon each other £ind upon other physical and chemical interferrents
will be optimally decoupled from each other. For example, if, in the chemistry system
30 of the amperometric cell, bilirubin and uric acid are chemical interferrents with each
other, a frequency or range of frequencies should be selected for the bilirubin
concentration determination, which frequency or range of frequencies is optimally

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unaffected by the concentrations of uric acid and any other physical and chemical
interferrents in the sample. Similarly, a frequency must be selected for the uric acid
concentration determination which is optimally unaffected by the concentrations of
bilirubin and any other physical and chemical interferrents in the sample. In each case,
5 however, the determined impedance is converted either directly or via a concentration
determination which can also be displayed to the user or stored in the instrument for
fixture reference, to a correction factor for application to the indicated glucose
concentration in order to arrive at a more accurate glucose concentration
determination.

10 The methods and apparatus are believed best understood by

consideration of the equivalent circuit of an amperometric sensor of the type described
inU. S. Patents: 5,243,516; 5,288,636; 5,352,351; 5,385,846; 5,508,171; 5,437,999;
and, U.S. S.N. 08/985,840. That equivalent circuit is illustrated in Fig. 1. In Fig. 1, a
resistor 20 represents the uncompensated resistance of the amperometric cell, a

15 capacitor 22 represents the capacitance attributable to the double layer of charge on
the dosed cell with potential applied, a resistor 24 represents the charge transfer
resistance of the cell's chemistry, and a resistor 26 and a capacitor 28 represent the so-
called Warburg impedance. While the lumped electrical parameter models of other
types of amperometric sensors may differ jfrom the model illustrated in Fig. 1, similar

20 analyses of those models will yield conclusions similar to those reached here, namely,
that the real and imaginary components of the cells' or biosensors' electrical
impedances provide techniques for determining quantitatively with some reasonable
degree of accuracy the effects of interferrent concentrations, sample volume and
sample identity on the concentration of a biologically significant component of a

25 sample of a body fluid. These conclusions give the instrument and cell designer useful
techniques for determining the adequacy of the volume of a sample appUed to a
biosensor, for determining the identity of the sample, and for correcting the indicated
concentration of a biologically significant component of the sample for the
concentration(s) of such interferrent(s) so that the effects of the concentration(s) of

30 such interferrent(s) can be reduced in the indicated concentration of the biologically
significant component of interest to provide more accurate information on the
concentration of the biologically significant component of interest.

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Blood sample studies analyzing the magnitudes of the real and
imaginary components of the impedance of the equivalent circuit of Fig. 1 have
estabUshed that in the range of about IKHz-lOKHz, there is very little dependence of
the imaginary component of impedance on glucose concentration of the sample, while
5 there is sufficient dependence of the magnitude of impedance on the combination of
sample temperature and hematocrit to permit a sample first to be subjected to a low-
magnitude AC signal in this frequency range, the magnitude of impedance to be
determined, and a combined sample temperature/hematocrit correction factor to be
combined with the indicated glucose concentration determined using the amperometry

10 techniques described in, for example, U. S. Patents: 5,243,516; 5,288,636; 5,352,351;
5,385,846; 5,508,171; 5,437,999; and, U.S.S.N. 08/985,840, to yield a glucose
concentration corrected for the combined effects of sample temperature and
hematocrit. Similar techniques can be employed to determine sample volume and
sample type. The sample volume determination, however, ordinarily will result in a

1 5 go-no go determination for the remainder of the assay. The sample type determination
ordinarily will determine whether the instrument proceeds to a glucose concentration
subroutine including, for example, determination of interferrent correction factors, or
to a diagnostic subroutine used to set up the instrument for a later glucose
concentration determination.

20 Referring to Fig. 2, a strip connector 30 of the general type illustrated

inU. S. Patents: 5,243,516; 5,288,636; 5,352,351; 5,385,846; and, 5,508,171, makes
contact between a disposable amperometric sensor cell or biosensor 3 1 of the general
type illustrated in those patents and the instrument 32. The indicated glucose
concentration fiinctionality of the instrument 32 is largely as described in those patents.

25 However, additional fianctions, namely, the correction of the indicated glucose

concentration for blood sample volume and the combined effect of sample temperature
and hematocrit of the blood sample under test, are implemented in the instrument 32
according to the present invention. It has been established that eight bit analog-to-
digital (A/D) and digital-to-analog (D/A) computational power permits the instrument

30 32 to achieve accuracies in the range of about one-half percent or less. A first terminal
34-1 of a connector 34 is coupled through a lOKQ resistor to a terminal 36-1 of a
switch 36. A terminal 36-2 of switch 36 is coupled to the inverting, or input

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terminal of a difference amplifier 38. An output terminal of amplifier 38 is coupled to
a terminal 36-3 of switch 36. A terminal 36-4 of switch 36 is coupled to a terminal 34-
2 of connector 34. DC excitation across the biosensor 3 1 is established by the output
of amplifier 38. For accurate setting of DC excitation of the biosensor 31, feedback
5 from terminal 34-1 is returned to the - input terminal of amplifier 38, Terminals 34-1
and 34-2 contact a common electrode on biosensor 3 1 for enhanced accuracy of
excitation.

A terminal 34-3 of connector 34 is coupled to a - input terminal of a
difference amplifier 42. An output terminal of amplifier 42 is coupled through a 7.5KQ

10 resistor 44 to the - input terminal thereof The non-inverting, or +, input terminal of
amplifier 42 is coupled to the common of the circuit power supply. An output terminal
of amplifier 42 is coupled to an input terminal of a thirteen bit A/D converter 46. An
output port of A/D converter 46 is coupled to an input port of a processor 48 with
supporting fimctions which performs the indicated glucose measurement fimctions as

15 described in U. S. Patents: 5,243,516; 5,288,636; 5,352,351; 5,385,846; and,

5,508,171. An output port of processor 48 is coupled to an input port of an eight bit
D/A converter 50. An output terminal of D/A converter 50 is coupled to the + input
terminal of amplifier 38. The fiinctions of components 38, 42, 46, 48 and 50
illustratively, although not by any means necessarily, are embodied in an application-

20 specific integrated circuit(ASIC) 52. The remaining, hematocrit compensating and

sample volume determining fiinctions of instrument 32 illustratively are embodied in a
NEC |aPD78054 microprocessor(nP) 54 which also has input A/D and output D/A
converting capabilities 56 and 58, respectively. In Fig. 2, the input A/D and output
D/A capabilities 56, 58 are illustrated separately from the processing fiinctions of (iP

25 54 for purposes of clarity. Terminal 36-4 of switch 36 is coupled to an input terminal
of A/D converter 56. The output terminal of amplifier 42 is coupled to an input
terminal of A/D converter 56. The output terminal of D/A converter 58 is coupled
through a . 1 ^F capacitor and a 400KQ resistor in series to terminal 36-1 of switch 36
for AC excitation in this example. Here, an AC excitation signal is summed with the

30 DC excitation provided by amplifier 38.

The calculations of the real and imaginary components of the AC
impedance of the biosensor cell 3 1 coupled to terminals 34-1, -2 and -3 are made by

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exciting terminal 34-2 of connector 34 at the desired frequency, for example, 1300Hz
or 10 KHz, at which the parameter to be determined, be it sample identity or volume
or hematocrit, or whatever other parameter is of interest and can be determined this
way, varies with sufficient magnitude and phase and is optimally uncoupled from, that
5 is, is not interfered with by, the concentrations of other components of the blood on
the cell 31.

The calculation of the real and imaginary components of the cell 3 1
impedance from the AC excitation and response are achieved as follows. The eight bit
excitation samples are N values E(0), E(l), E(2), . . . E(N-l). These values are

10 developed by sampling the excitation by A/D converter 56. The eight bit response

samples are N values V(0), V(l), V(2), . . . V(N-1). These values are A/D converted
by A/D converter 56 and returned to the processor function of |iP 54. Terminal 34-2
of connector 34 provides the common terminal against which these values are
referenced. A scale factor K accounts for various gain factors involved in excitation

15 and measurement. The excitation frequency is F Hz. The sample rate is MF, where M
illustratively has a value of 5 or more. The period between samples is thus 1/MF sec.
Arrays S(n) and C(n) of sine and cosine values are calculated and stored in program
memory in ^P 54 according to the following relations:

20 S(n) = sin(27TF(n/MF)), n=0 to (N-1)

C(n)-cos(27uF(n/MF)), n=0 to (N-1).

The real and imaginary components of excitation are calculated as

25 follows:

7^-1

«=o

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The real and imaginary components of response are calculated as
Eim=Y, C{ri)E(n)

follows:

Vre=Y, S(n)V(n)

77=0

N-\

Vim=J2 C{n)V{n)
The magnitudes of the excitation and response are calculated as

follows:

E-CEre'+Eim^)'^,
V=(Vre^+Vim2)'^l
The magnitude of the strip impedance can then be calculated:

|Z|=KE/V.

The phase of the strip impedance can also be calculated:

arctan /Vim\ - arctanMni = Z_Z
IVre/ \&e/

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Thus, a measurement of actual glucose concentration using an
instrument 32 of the type illustrated in Fig. 2 proceeds as follows. A sample of blood
is applied to the biosensor 3 1 . Immediately after the instrument 32's electronics detect
the deposit of the droplet on the biosensor 3 1, an AC signal having a frequency of, for
5 example, 1300Hz is applied across terminals 34-2—34-3 of connector 34 and the
resulting current is indirectly sampled by ^iP 54 by measuring the excitation and
response voltages and using the scale factor to obtain current. The impedance
magnitude and phase angle are calculated. Using these values, a look-up table in the
|iiP 54' s program memory is consulted to ascertain the nature of the sample and, if

1 0 blood, whether there is suflScient volume in the blood sample to proceed with the
glucose determination phase of the assay. If not, the assay is terminated and this
outcome is displayed on the instrument 32's display. If there is sufficient volume to
continue with the glucose determination, an AC signal at another frequency, for
example, 10 KHz, is applied across terminals 34-2—34-3 of connector 34 and the

15 resulting current is sampled by ^iP 54. The impedance and phase angle are again

calculated at this second frequency. A second look-up table in the |liP 54's program
memory is consulted for an indicated glucose-to-actual glucose correction factor. This
correction factor may be a constant, for example, zero, for indicated glucose
concentrations less than a first indicated glucose concentration, and variable for

20 indicated glucose concentrations greater than that first indicated glucose concentration,
for example. In any event, that correction is stored, and the determination of the
indicated glucose concentration proceeds generally as described in U. S. Patents:
5,243,516; 5,288,636; 5,352,351; 5,385,846; and 5,508,171, for example. Once the
indicated glucose concentration has been obtained, the correction is then retrieved and

25 applied to the indicated glucose concentration to arrive at the actual glucose

concentration which is displayed on the instrument 32's display and/or stored in the
instrument 32's memory.

Another embodiment of the invention is illustrated in partly block and
partly schematic form in Fig. 3. There, an instrument 132 includes a strip connector

30 130 of the same general type as strip connector 30 illustrated in Fig. 2. Strip

connector 130 is designed to make contact to a biosensor 3 1. A first terminal 134-1 of
a coimector 134 is coupled through a lOKQ resistor to a terminal 136-1 of a switch

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136. A terminal 136-2 of switch 136 is coupled to the - input terminal of a difference
amplifier 138. An output terminal of amplifier 138 is coupled to a terminal 136-3 of
switch 136. A terminal 136-4 of switch 136 is coupled to a terminal 134-2 of
connector 134. DC excitation across the biosensor 3 1 is established by the output of
5 amplifier 138. For accurate setting of DC excitation of the biosensor 31, feedback
from terminal 134-1 is returned to the - input terminal of ampHfier 138. Terminals
134-1 and 134-2 contact a common electrode on biosensor 31 for enhanced accuracy
of excitation. A terminal 134-3 of connector 134 is coupled to a - input terminal of a
difference amplifier 142. An output terminal of amplifier 142 is coupled through a

10 7.5KQ resistor 144 to the - input terminal thereof The + input terminal of amplifier
142 is coupled to the common of the circuit power supply. An output terminal of
amplifier 142 is coupled to an input terminal of a thirteen bit A/D converter 146. An
output port of A/D converter 146 is coupled to an input port of a processor 148 with
supporting fijnctions which performs the indicated glucose measurement fiinctions as

15 described in U. S. Patents: 5,243,516; 5,288,636; 5,352,351; 5,385,846; and,

5,508, 171 . An output port of processor 148 is coupled to an input port of an eight bit
D/A converter 150. An output terminal of D/A converter 150 is coupled to the + input
terminal of amplifier 138. The fiinctions of components 138, 142, 146, 148 and 150
illustratively, although not by any means necessarily, are embodied in an ASIC 152.

20 The real and imaginary components of the AC impedance of the

biosensor cell 31 coupled to terminals 134-1, -2 and -3 are calculated by excitation
applied between terminals 134-2 and 134-3 of connector 134 at the desired
frequencies, for example, by sweeping the low-magnitude AC voltage source 150
through a suitable frequency range of, for example, .1 Hz - 100 Hz or lOHz - 10 KHz,

25 throughout some portion or all of which the parameter to be determined, be it sample
identity, sample volume, sample temperature/hematocrit, oxygen concentration in the
sample, or whatever other parameter is of interest and can be determined this way,
varies with suflBcient magnitude and phase and is optimally uncoupled from, that is,
independent from, the concentrations of other components of the sample on the

30 cell 31.

In the embodiment illustrated in Fig. 3, this low magnitude AC voltage
excitation is summed at a summing junction 152 with an optional DC offiset 156 which

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may be utilized if it aids the determination of the concentration of the interferent of
interest. In the illustrated embodiment, the AC voltage and DC offset are both
generated under the control of a microprocessor ((iP) 158 which may be the same |liP
which manages the above-mentioned meter 132 functions, or may be a separate iiP.
5 The (aP 158 will typically be programmed to sweep the AC voltage source 150 and
adjust the DC offset, depending upon which interferent' s concentration the \xP 158 is
determining. In this manner, each interferent' s concentration may readily be
ascertained in the optimum frequency range and at the optimum DC offset for isolation
of that particular interferent 's concentration. If |liP 158 is used to control sweep and

10 oflfset, a separate external connection 160 need not be provided from the summing
junction 152 to the |iP 158. Since |iP 158 is going to determine the frequency
response of the cell 3 1, the frequencies associated with the determined frequency
response can be stored in the \iP 158's memory as the frequency response is being
determined. If some other mechanism is employed in the determination of the

15 frequency response, however, it may be necessary to provide feedback 160 to the |iP
158 of the output frequency of source 150, as well as the level of the DC offset 156.
In any event, isolation of the summing junction 152 and any feedback path 160 from
the cell 3 1 is provided by an operational amplifier 164 whose input is coupled to
summing junction 152, and whose output is coupled through a suitably valued resistor

20 into the feedback path of amplifier 138 to drive the cell 3 1 . Similarly, isolation of the
cell 3 1 from the frequency response-determining input of |iP 158 is provided by an
operational amplifier 166 coupled to the output of amplifier 142. Determination of the
frequency response of the cell 3 1 proceeds in known fashion, for example, by fast
Fourier transform (FFT) or other known |liP 158-impiemented frequency response

25 determining mechanism. The frequency response characteristic of the cell 3 1 is then
compared to the stored frequency response characteristic for the specific interferent
whose concentration is being determined, an interferent concentration is determined,
and an associated correction value for the indicated glucose concentration is
determined and either stored for later use in correcting the indicated glucose

30 concentration or immediately combined with an indicated glucose concentration to
achieve a corrected glucose concentration.

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Again, ordinarily, the instrument 132 will first determine the various
frequency responses of the cell 3 1 in the various optimally uncoupling frequency
ranges, with the various optimally uncoupling AC amplitudes and with the various
optimally uncoupling DC offsets, followed by the determination of the indicated
5 glucose concentration, followed by correction of the indicated glucose concentration
for the thus-determined concentrations of the various interferrents. However, and as
previously noted, it may be desirable under certain circumstances and with certain
interferrents to have the instrument 132 first determine the indicated concentration of
glucose before the concentrations of these interferrents are determined.

1 0 Another embodiment of the invention is illustrated in partly block and

partly schematic form in Fig. 4. There, an instrument 232 includes a strip connector
230 of the same general type as strip connector 30 illustrated in Fig. 2. Strip
connector 230 is designed to make contact to a biosensor 31. A first terminal 234-1 of
a connector 234 is coupled to the - input terminal of a difference amplifier 238. An

15 output terminal of amplifier 238 is coupled to a terminal 234-2 of connector 234. DC
excitation across the biosensor 3 1 is established by the output of ampHfier 238. For
accurate setting of DC excitation of the biosensor 3 1, feedback from terminal 234-1 is
returned to the - input terminal of amplifier 238. Terminals 234-1 and 234-2 contact a
common electrode on biosensor 3 1 for enhanced accuracy of excitation. A terminal

20 234-3 of connector 234 is coupled to a - input terminal of a difference amplifier 242.
An output terminal of amplifier 242 is coupled through a 8.25KQ resistor 244 to the -
input terminal thereof The + input terminal of amplifier 242 is coupled to a 1 .667V
reference. An output terminal of amphfier 242 is coupled to an input terminal of a
fourteen bit A/D converter 246. An output port of A/D converter 246 is coupled to an

25 input port of a processor 248 with supporting functions which performs the indicated
glucose measurement functions as described inU. S. Patents: 5,243,516; 5,288,636;
5,352,351; 5,385,846; and, 5,508,171. An output port of processor 248 is coupled to
an input port of a thirteen bit D/A converter 250. Amplifier 238 and D/A converter
250 illustratively are integrated into a single device. Amplifier 238 has an open circuit

30 shutdown mode, permitting switches 36, 136 of the embodiments illustrated in Figs. 2-
3 to be eliminated and thereby simplifying the circuit somewhat. Otherwise, the circuit
illustrated in Fig. 4 functions in much the same way as the circuits illustrated in Figs. 2-

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3. An output terminal of D/A converter 250 is coupled to the + input terminal of
amplifier 238. The functions of components 238, 242, 246, 248 and 250 illustratively,
although not by any means necessarily, are embodied in an ASIC 252. The accuracy
and resolution of D/A converter 250 and A/D converter 246 enable both AC and DC
5 strip current measurements and thus a circuit simplification.

Again, it should be understood that the physical and chemical design
characteristics of a particular cell will, to a large extent, determine the electrical
characteristics of that cell. Therefore, those physical and chemical design
characteristics will, to at least the same extent, determine that cell's response to each

10 interferent, to different sample types, and to different sample volumes. It is not

possible to predict, for example, in what fi-equency range hematocrit's concentration
will be optimally uncoupled from uric acid's or bilirubin's without reference to the
specific physical and chemical characteristics of that cell. Some investigation will be
required to determine these optimum frequency ranges. However, the investigation

15 will be relatively routine once the physical and chemical characteristics of the cell are
known.

The reduction in the time required to achieve a compensated indication
of the glucose concentration of blood can best be appreciated by referring to Figs. 5-7.
Fig. 5 illustrates glucose concentration results achieved in several forty second glucose

20 concentration determinations with standard glucose test solutions. The tests whose
results are illustrated in Fig. 5 were performed without impedance determination and
compensation for the combined effects of temperature and hematocrit described above,
but were compensated for temperature and hematocrit using prior art techniques.
Fig. 6 illustrates glucose concentration results achieved in several ten second glucose

25 concentration determinations with standard glucose test solutions. The tests whose
results are illustrated in Fig. 6 were performed without impedance determination and
compensation for the combined effects of temperature and hematocrit described above,
but again were compensated for temperature and hematocrit using prior art techniques.
Fig. 7 illustrates glucose concentration results achieved in several ten second glucose

30 concentration determinations with standard glucose test solutions. The tests whose
results are illustrated in Fig. 7 were performed using impedance determination and
compensation for the combined effects of temperature and hematocrit described above.

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It will be appreciated from a comparison of these Figs, that the use of the impedance
determination and compensation technique described above permits a reduction by a
factor of four in the time required to achieve comparable glucose concentration
determination in these test solutions.

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CLAIMS

1 . An apparatus for determining the concentration of a medically
significant component of a biological fluid, the apparatus comprising a cell for

5 receiving a sample of the fluid, the cell supporting a chemistry which reacts with the
medically significant component and first and second terminals across which the
reaction of the chemistry with the medically significant component can be assessed, an
instrument having first and second terminals complementary to the first and second
terminals, respectively, of the cell, placement of the first and second terminals of the

10 cell in contact with the first and second terminals, respectively, of the instrument

permitting the instrument to assess the reaction, the instrument including an assessment
controller for applying across the first and second terminals of the instrument a first
signal, determining a first correction value in response of the cell to the first signal,
assessing the reaction of the medically significant component with the chemistry and

15 combining the correction value with the result of the reaction assessment to produce
an indication of the concentration of the medically significant component in the sample.

2. The apparatus of claim 1 wherein the assessment controller
comprises an assessment controller for applying across the first and second terminals a
signal having an AC component.

20 3, The apparatus of claim 2 wherein the assessment controller

comprises an assessment controller for applying across the first and second terminals
an AC signal.

4. The apparatus of claim 1 wherein the instrument fiirther
comprises a third terminal, placement of the first and second terminals of the cell in

25 contact with the first and second terminals of the instrument placing one of the first
and second terminals of the cell in contact with the third terminal of the instrument.

5. The apparatus of claim 4 wherein the assessment controller for
determining a first correction value in response to the first signal comprises an
assessment controller for feeding back a portion of the first signal appearing at the

30 third terminal,

6. The apparatus of claim 5 wherein the assessment controller for
assessing the reaction of the medically significant component with the chemistry

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comprises an assessment controller for appljdng across a pair of the first, second and
third terminals of the instrument a second signal and assessing the reaction of the
medically significant component with the chemistry in response to the second signal.

7. The apparatus of claim 1 wherein the assessment controller for
5 applying across the first and second terminals of the instrument a first signal comprises
an assessment controller for applying across the first and second terminals of the
instrument a second signal, determining a second response to the second signal, the
second response determining if the assessment controller proceeds with the application
of the first signal.

10 8. The apparatus of claim 7 wherein the assessment controller for

applying across the first and second terminals of the instrument a second signal
comprises an assessment controller for applying across the first and second terminals a
signal having an AC component.

9. The apparatus of claim 8 wherein the assessment controller for
15 applying across the first and second terminals of the instrument a second signal

comprises an assessment controller for applying across the first and second terminals
an AC signal.

10. The apparatus of claim 2 wherein the instrument fiirther
comprises a third terminal, placement of the first and second terminals of the cell in

20 contact with the first and second terminals of the instrument placing one of the first
and second terminals of the cell in contact with the third terminal of the instrument.

1 1 . The apparatus of claim 10 wherein the assessment controller for
determining a first correction value in response to the first signal comprises an
assessment controller for feeding back a portion of the first signal appearing at the

25 third terminal.

12. The apparatus of claim 1 1 wherein the assessment controller for
assessing the reaction of the medically significant component with the chemistry
comprises an assessment controller for applying across a pair of the first, second and
third terminals of the instrument a second signal and assessing the reaction of the

30 medically significant component with the chemistry in response to the second signal.

13. An apparatus for determining the concentration of a medically
significant component of a biological fluid, the apparatus comprising a cell for

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receiving a sample of the fluid, the cell supporting a chemistry which reacts with the
medically significant component and first and second terminals across which the
reaction of the chemistry with the medically significant component can be assessed, an
instrument having first and second terminals complementary to the first and second
5 terminals, respectively, of the cell, placement of the first and second terminals of the
cell in contact with the first and second terminals, respectively, of the instrument
permitting the instrument to assess the reaction, the instrument including an assessment
controller for applying across the first and second terminals of the instrument a first
signal having an AC component, determining a first response of the cell to the first
10 signal, and determining based upon the first response whether to proceed with the
determination of the concentration of the medically significant component of the
biological fluid.

14. The apparatus of claim 13 wherein the assessment controller for
applying across the first and second terminals of the instrument a first signal comprises

15 an assessment controller for applying across the first and second terminals an AC
signal,

15. The apparatus of claim 13 wherein the assessment controller for
applying across the first and second terminals of the instrument a first signal comprises
an assessment controller for applying across the first and second terminals of the

20 instrument a second signal, determining a first correction value in response to the
second signal, and combining the correction value with the result of the reaction
assessment to produce an indication of the concentration of the medically significant
component in the sample.

16. The apparatus of claim 15 wherein the assessment controller for
25 applying across the first and second terminals a second signal comprises an assessment

controller for applying across the first and second terminals a second signal having an
AC component.

17. The apparatus of claim 16 wherein the assessment controller for
applying across the first and second terminals a second signal comprises an assessment

30 controller for applying across the first and second terminals an AC second signal.

18. The apparatus of claim 17 wherein the instrument fiirther
comprises a third terminal, placement of the first and second terminals of the cell in

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contact with the first and second terminals of the instrument placing one of the first
and second terminals of the cell in contact with the third terminal of the instrument.

19. The apparatus of claim 18 wherein the assessment controller for
determining a first correction value in response to the second signal comprises an

5 assessment controller for feeding back a portion of the second signal appearing at the
third terminal.

20. The apparatus of claim 19 wherein the assessment controller for
assessing the reaction of the medically significant component with the chemistry
comprises an assessment controller for applying across a pair of the first, second and

1 0 third terminals of the instrument a third signal and assessing the reaction of the

medically significant component with the chemistry in response to the second signal.

2 1 . The apparatus of claim 1 5 wherein the instrument fijrther
comprises a third terminal, placement of the first and second terminals of the cell in
contact with the first and second terminals of the instrument placing one of the first

15 and second terminals of the cell in contact with the third terminal of the instrument.

22. The apparatus of claim 21 wherein the assessment controller for
determining a first correction value in response to the second signal comprises an
assessment controller for feeding back a portion of the second signal appearing at the
third terminal.

20 23 . The apparatus of claim 22 wherein the assessment controller for

assessing the reaction of the medically significant component with the chemistry
comprises an assessment controller for applying across a pair of the first, second and
third terminals of the instrument a third signal and assessing the reaction of the
medically significant component with the chemistry in response to the third signal.

25 24. A method for determining the concentration of a medically

significant component of a biological fluid, the method comprising providing a cell for
receiving a sample of the fluid, providing on the cell a chemistry which reacts with the
medically significant component and first and second terminals across which the
reaction of the chemistry with the medically significant component can be assessed,

30 providing an instrument having first and second terminals complementary to the first
and second terminals, respectively, of the cell, placement of the first and second-
terminals of the cell in contact with the first and second terminals, respectively, of the

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instrument permitting the instrument to assess the reaction, including in the instrument
an assessment controller, causing the assessment controller to apply across the first and
second terminals of the instrument a first signal having an AC component, causing the
assessment controller to determine a first response of the cell to the first signal, and
5 causing the assessment controller to determine based upon the first response whether
to proceed with the determination of the concentration of the medically significant
component of the biological fluid.

25. The method of claim 24 wherein the step of applying across the
first and second terminals of the instrument a first signal comprises applying across the

10 first and second terminals of the instrument a second signal, determining a first

correction value in response to the second signal, and combining the first correction
value with the result of the reaction assessment to produce an indication of the
concentration of the medically significant component in the sample.

26. The method of claim 25 wherein the step of applying across the
15 first and second terminals a second signal comprises applying across the first and

second terminals an AC second signal.

27. The method of claim 26 wherein providing an instrument having
first and second terminals complementary to the first and second terminals of the cell
comprises providing an instrument having first, second and third terminals, placement

20 of the first and second terminals of the cell in contact with the first, second and third
terminals of the instrument permitting the instrument to assess the reaction.

28. The method of claim 27 wherein determining the second
response of the cell to the second signal and converting that second response to a first
correction value comprises feeding back a portion of the second signal appearing at the

25 third terminal.

29. The method of claim 28 wherein assessing the reaction of the
medically significant component with the chemistry comprises applying across a pair of
the first, second and third terminals of the instrument a third signal and assessing the
reaction of the medically significant component with the chemistry in response to the

30 third signal.

30. The method of claim 24 wherein providing an instrument having
first and second terminals complementary to the first and second terminals.

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respectively, of the cell comprises providing an instrument having first, second and
third terminals, placement of the first and second terminals of the cell in contact with
the first and second terminal of the instrument placing one of the first and second
terminals of the cell in contact with the third terminal of the instrument.
5 31. The method of claim 30 wherein determining the correction

value in response to the second signal comprises feeding back a portion of the second
signal appearing at the third terminal.

32. The method of claim 3 1 wherein assessing the reaction of the
medically significant component with the chemistry comprises applying across a pair of

10 the first, second and third terminals of the instrument a third signal and assessing the
reaction of the medically significant component with the chemistry in response to the
third signal.

33 . A method for determining the concentration of a medically
significant component of a biological fluid, the method comprising providing a cell for

15 receiving a sample of the fluid, providing the cell with a chemistry which reacts with
the medically significant component and first and second terminals across which the
reaction of the chemistry with the medically significant component can be assessed,
providing an instrument having first and second terminals complementary to the first
and second terminals, respectively, of the cell, placement of the first and second

20 terminals of the cell in contact with the first and second terminals, respectively, of the
instrument permitting the instrument to assess the reaction, providing in the instrument
an assessment controller, causing the assessment controller to apply across the first and
second terminals of the instrument a first signal, determining a first correction value in
response to the first signal, assessing the reaction of the medically significant

25 component with the chemistry, and combining the correction value with the result of
the reaction assessment to produce an indication of the concentration of the medically
significant component in the sample.

34. The method of claim 33 wherein providing an instrument having
first and second complementary terminals comprises providing an instrument having

30 first, second and third terminals, placement of the first and second terminals of the cell
in contact with the first and second terminals, respectively, of the instrument placing

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one of the first and second terminals of the cell in contact with the third terminal of the
instrument.

35. The method of claim 34 wherein determining a first response of
the cell to the first signal and converting that first response to a first correction value
comprises feeding back a portion of the first signal appearing at the third terminal.

36. The method of claim 35 wherein assessing the reaction of the
medically significant component with the chemistry comprises applying across a pair of
the first, second and third terminals of the instrument a second signal and assessing the
reaction of the medically significant component with the chemistry in response to the
second signal.

37. The method of claim 33 wherein applying across the first and
second terminals of the instrument a first signal comprises applying across the first and
second terminals of the instrument a second signal, determining a second response to
the second signal, and determining if the assessment controller proceeds with the
application of the first signal.

38. The method of claim 33, 34, 35 36 or 37 wherein applying the
first signal comprises applying a first signal having an AC component.

39. The method of claim 33, 34, 35, 36 or 37 wherein applying the
first signal comprises applying a first AC signal.

40. The method of claim 37 wherein applying a second signal
comprises applying a second signal having an AC component.

41 . The method of claim 40 wherein applying a second signal
comprises applying an AC second signal.

42. An apparatus for determining the concentration of a medically
significant component of a biological fluid comprising a cell for receiving a sample of
the fluid, the cell supporting a chemistry which reacts with the medically significant
component and first and second terminals across which the reaction of the chemistry
with the medically significant component can be assessed, an instrument having first
and second terminals complementary to the first and second terminals, respectively, of
the cell, placement of the first and second terminals of the cell in contact with the first
and second terminals, respectively, of the instrument permitting the instrument to
assess the reaction, the instrument including an assessment controller for applying

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across the first and second terminals of the instrument a first signal, for determining the
identity of the sample in response of the cell to the first signal, and for producing an
indication of the identity of the sample.

43. The apparatus of claim 42 wherein the assessment controller

5 comprises an assessment controller for applying across the first and second terminals a
signal having an AC component.

44. The apparatus of claim 43 wherein the assessment controller
comprises an assessment controller for applying across the first and second terminals
an AC signal.

10 45 . The apparatus of claim 42 wherein the instrument fiirther

comprises a third terminal, placement of the first and second terminals of the cell in
contact with the first and second terminals of the instrument placing one of the first
and second terminals of the cell in contact with the third terminal of the instrument, the
assessment controller applying across a pair of the first, second and third terminals of

15 the instrument a second signal, determining a first correction value in response of the
cell to the second signal, assessing the reaction of the medically significant component
with the chemistry, and combining the correction value with the result of the reaction
assessment to produce an indication of the concentration of the medically significant
component in the sample.

20 46. The apparatus of claim 45 wherein the assessment controller for

assessing the reaction of the medically significant component with the chemistry
comprises an assessment controller for applying across a pair of the first, second and
third terminals of the instrument a third signal, determining a third response to the third
signal, the third response determining if the assessment controller proceeds with the

25 application of at least one of the first and second signals.

47. The apparatus of claim 42 wherein the assessment controller
fijrther comprises a third terminal, placement of the first and second terminals of the
cell in contact with the first and second terminals of the instrument placing one of the
first and second terminals of the cell in contact with the third terminal of the

30 instrument, the assessment controller applying across a pair of the first, second and

third terminals of the instrument a second signal, determining a second response to the

wo 99/32881 PCT/US98/27203

-29-

second signal, the second response determining if the assessment controller proceeds
with the application of the first signal.

48. A method for determining the concentration of a medically
significant component of a biological fluid comprising providing a cell for receiving a
5 sample of the fluid, providing on the cell a chemistry which reacts with the medically
significant component and first and second terminals across which the reaction of the
chemistry with the medically significant component can be assessed, providing an
instrument having first and second terminals complementary to the first and second
terminals, respectively, of the cell, placement of the first and second terminals of the

10 cell in contact with the first and second terminals, respectively, of the instrument
permitting the instrument to assess the reaction, providing in the instrument an
assessment controller for applying across the first and second terminals of the
instrument a first signal, determining the identity of the sample in response of the cell
to the first signal, and producing an indication of the identity of the sample.

15 49. The method of claim 48 wherein the step of providing an

instrument having first and second terminals comprises the step of providing an
instrument having first, second and third terminals, placement of the first and second
terminals of the cell in contact with the first and second terminals of the instrument
placing one of the first and second terminals of the cell in contact with the third

20 terminal of the instrument, the assessment controller applying across a pair of the first,
second and third terminals of the instrument a second signal, determining a first
correction value in response of the cell to the second signal, assessing the reaction of
the medically significant component with the chemistry, and combining the correction
value with the result of the reaction assessment to produce an indication of the

25 concentration of the medically significant component in the sample.

50. The method of claim 49 wherein the assessment controller
applies across a pair of the first, second and third terminals of the instrument a third
signal and determines a third response to the third signal, the third response
determining if the assessment controller proceeds with the application of at least one of

30 the first and second signals.

5 1 . The method of claim 48 wherein the step of providing an
instrument having first and second terminals comprises the step of providing an

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-30-

instrument having first, second and third terminals, placement of the first and second
terminals of the cell in contact with the first and second terminals of the instrument
placing one of the first and second terminals of the cell in contact with the third
terminal of the instrument, the assessment controller applying across a pair of the first,
5 second and third terminals of the instrument a second signal and determining a second
response to the second signal, the second response determining if the assessment
controller proceeds with the application of the first signal.

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PCTAJS98/27203

INTERNATIONAL SEARCH REPORT

Intemationai application No.
PCT/US98/27203

A. CLASSIFICATION OF SUBJECT MATTER

IPC(6) : GOIN 27/26, 27/02, 27/28

US CL ; 324/444; 204/401, 403; 205/775
Aooording to International Patent Clagaification (IPC) or to both national classification and IPC

FIELDS SEARCHED

Minimum documentation searched (classification system followed by classification symbols)
U.S. : 324/444; 204/401, 403; 205/775

Documentation searched other than minimum documentation to the extent that such documenU are included in the fidds searched

Electronic daU base consuhed during the intmiational search (name of data base and, where practicable, seaivh tenns used)
Please See Extra Sheet.

C. DOCUMENTS CONSIDERED TO BE RELEVANT

Category^

Citation of document, with indication, where appropriate, of the relevant passages

Relevant to claim No.

X
Y

US 4,652,830 A (BROWN) 24 March 1987 (24/3/87), see abstract;
Figures lA-lC, 2, 8A-8E, and lOA-lOC; column 1, lines 42-64; coL
2, In. 11-15, In. 21-23; col. 4, In. 46-56; and col, 5, In. 40-45; col.
5, In. 63 - col. 6, In. 25; col. 15, In. 8 - coL 16, In. 55; and col.
16, In. 56 - col. 17, In. 52.

US 4,713,347 A (MITCHELL ET AL.) 15 December 1987
(15/12/87), column 38, Unes 20-25; and col. 40, In. 46-51.

1-41
42-51

42-51

I x| Further documents are listed in the continuation of Box C. | | See patent family annex.

Special categortet of cited document*:

' documeot defining the general state of the art which is not considered

to be of particular relevance

"E" earlier document published on or after the intemationai filing date

"L" document which may throw doubts on priority ciaim(s) or which is

cited to establish the publication date of another citation or other
special reason (as specified)

"O* document referring to an oral disclosure, use, exhibition or other

means

•P* document published prior to the intemationai filing date but latar than
the priority date claimed

later document published after the intemationai filing date or priority
dattt and not in conflict with the application but cited to understand
the principle or theory underlying the invention

document of particular relevance; the claimed invention cannot be
considered novel or cannot be considered to involve an inventive step
when the document ti taken alone

document of particular relevance; the claimed invention cannot be
considered to involve an inventive step when the document is
combined with one or more other such documents, such combination
being obvious to a person skilled in the art

document member of the same patent family

Date of the actual completion of the intemationai search

08 MARCH 1999

Name and mailing address of the ISA/US
Commissioner of Patents and Trademarks

Box PCT

Washington, D.C. 20231
Facsimile No. (703) 305-3230

Date of mailing of the intemationai search report

09 APR 1399

ALEXANDER NOGUEROL/
Telephone No. (703) 308-0661

Forni PCT/ISA/210 (second sheet)(July 1992)*

INTERNATIONAL SEARCH REPORT

International appUcation No.
PCT/US98/27203

B. HELDS SEARCHED

Electronic data bases consulted (Name of data base and where practicable terms used):
CAPLUS

search terms: AC, altemating current, alternating voltage, impedance, imaginaiy, electrode, blood, glucose, oxidase,
oxidoreductase

Form PCT/ISA/210 (extra shcet)(July 1992)*

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